Abstract
Yes-associated protein 1 (YAP1) acts as an oncogene through dephosphorylation and nuclear translocation, and nuclear accumulation of YAP1 is associated with poor prognosis in gastric cancer (GC). We previously identified ivermectin, an antiparasitic drug, as a YAP1 inhibitor. Here, we aimed to clarify whether ivermectin had antitumor effects on GC through inhibition of YAP1. First, we evaluated the antiproliferative effects of ivermectin on human GC cells using in vitro proliferation assays and a xenograft mouse model. YAP1-knockdown assays were performed to assess whether the sensitivity to ivermectin depended on YAP1 expression. Next, we explored the mechanism through which ivermectin regulated YAP1 expression or localization by immunoblotting and reverse transcription-quantitative polymerase chain reaction for YAP1 and the downstream gene CTGF. Finally, the clinical significance of YAP1 expression was examined using three independent GC datasets. We found that MKN1 GC cells were most sensitive to ivermectin, whereas MKN7 cells were most resistant. In MKN1 xenografts, ivermectin suppressed tumor growth, and the sensitivity of MKN1 cells to ivermectin was decreased by YAP1 knockdown. Ivermectin inhibited YAP1 nuclear expression and CTGF expression in MKN1 cells but not MKN7 cells. Moreover, ivermectin decreased YAP1 mRNA expression, thereby inhibiting nuclear accumulation of YAP1 in MKN1 cells. In survival analysis, low YAP1 mRNA expression was associated with a better prognosis in three independent GC datasets. In conclusion, we identified ivermectin as a potential antitumor agent and found a promising novel therapeutic strategy for inhibition of GC progression by blocking YAP1 expression.
Highlights
Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer-related death worldwide [1]
Among the tested cell lines, we found that MKN1 cells were most sensitive to ivermectin (IC50 = 10.2 μM) and that SH10-TC cells were sensitive to the drug (IC50 = 21.2 μM; Figure 1A)
Ivermectin suppressed the proliferation of gastric cancer (GC) cells in vitro by decreasing nuclear expression of Yes-associated protein 1 (YAP1) in a concentration- and time-dependent manner
Summary
Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer-related death worldwide [1]. Increased nuclear expression of YAP1 is associated with poor prognosis in patients with GC [3, 4], colon cancer, ovarian cancer, and lung cancer [5,6,7]. YAP1 is a downstream target of the Hippo signaling pathway, which regulates organ size during development [8]. YAP1 acts as a transcriptional co-activator in the nucleus, activating TEA domain transcription factor (TEAD)-mediated transcription of cell proliferation genes, such as connective tissue growth factor (CTGF) [9]. Nuclear YAP1 is a positive regulator of cell proliferation that is suppressed by Hippo signaling. Inhibition of YAP1 expression may prevent tumor progression and improve prognosis in various malignancies, including GC [3,4,5,6,7]
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